Genome-wide association studies have described several genes as genetic susceptibility loci for Alzheimer's disease (AD). Among them, CD2AP encodes CD2-associated protein, a scaffold protein implicated in dynamic actin remodeling and membrane trafficking during endocytosis and cytokinesis. Although a clear link between CD2AP defects and glomerular pathology has been described, little is known about the function of CD2AP in the brain. The aim of this study was to analyze the distribution of CD2AP in the AD brain and its potential associations with tau aggregation and β-amyloid (Aβ) deposition. First, we performed immunohistochemical analysis of CD2AP expression in brain tissue from AD patients and controls (N = 60). Our results showed granular CD2AP immunoreactivity in the human brain endothelium in all samples. In AD cases, no CD2AP was found to be associated with Aβ deposits in vessels or parenchymal plaques. CD2AP neuronal inclusions similar to neurofibrillary tangles (NFT) and neuropil thread-like deposits were found only in AD samples. Moreover, immunofluorescence analysis revealed that CD2AP colocalized with pTau. Regarding CD2AP neuronal distribution, a hierarchical progression from the entorhinal to the temporal and occipital cortex was detected. We found that CD2AP immunodetection in neurons was strongly and positively associated with Braak neurofibrillary stage, independent of age and other pathological hallmarks. To further investigate the association between pTau and CD2AP, we included samples from cases of primary tauopathies (corticobasal degeneration [CBD], progressive supranuclear palsy [PSP], and Pick's disease [PiD]) in our study. Among these cases, CD2AP positivity was only found in PiD samples as neurofibrillary tangle-like and Pick body-like deposits, whereas no neuronal CD2AP deposits were detected in PSP or CBD samples, which suggested an association of CD2AP neuronal expression with 3R-Tau-diseases. In conclusion, our findings open a new road to investigate the complex cellular mechanism underlying the tangle conformation and tau pathology in the brain.

中文翻译：

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CD2AP 神经元沉积与阿尔茨海默病中 Braak 神经原纤维阶段的关联

全基因组关联研究已将几个基因描述为阿尔茨海默病 (AD) 的遗传易感基因座。其中，CD2AP编码 CD2 相关蛋白，这是一种参与内吞作用和胞质分裂过程中动态肌动蛋白重塑和膜运输的支架蛋白。尽管已经描述了 CD2AP 缺陷和肾小球病理学之间的明确联系，但对 CD2AP 在大脑中的功能知之甚少。本研究的目的是分析 CD2AP 在 AD 脑中的分布及其与 tau 聚集和 β-淀粉样蛋白 (Aβ) 沉积的潜在关联。首先，我们对 AD 患者和对照组脑组织中 CD2AP 的表达进行了免疫组织化学分析（N = 60)。我们的结果显示所有样本中人脑内皮细胞中的颗粒状 CD2AP 免疫反应性。在 AD 病例中，没有发现 CD2AP 与血管或实质斑块中的 Aβ 沉积相关。仅在 AD 样本中发现类似于神经原纤维缠结 (NFT) 和神经纤维线状沉积物的 CD2AP 神经元包涵体。此外，免疫荧光分析显示 CD2AP 与 pTau 共定位。关于 CD2AP 神经元分布，检测到从内嗅皮层到颞叶和枕叶皮层的分层进展。我们发现神经元中的 CD2AP 免疫检测与 Braak 神经原纤维分期强烈且呈正相关，与年龄和其他病理特征无关。为了进一步研究 pTau 和 CD2AP 之间的关联，我们在研究中纳入了原发性 tau 病变（皮质基底节变性 [CBD]、进行性核上性麻痹 [PSP] 和 Pick 病 [PiD]）病例的样本。在这些病例中，CD2AP 阳性仅在 PiD 样本中发现为神经原纤维缠结样和 Pick 体样沉积物，而在 PSP 或 CBD 样本中未检测到神经元 CD2AP 沉积物，这表明 CD2AP 神经元表达与 3R-Tau-疾病。总之，我们的研究结果为研究大脑中缠结构象和 tau 病理学背后的复杂细胞机制开辟了一条新途径。而在 PSP 或 CBD 样品中未检测到神经元 CD2AP 沉积物，这表明 CD2AP 神经元表达与 3R-Tau 疾病有关。总之，我们的研究结果为研究大脑中缠结构象和 tau 病理学背后的复杂细胞机制开辟了一条新途径。而在 PSP 或 CBD 样品中未检测到神经元 CD2AP 沉积物，这表明 CD2AP 神经元表达与 3R-Tau 疾病有关。总之，我们的研究结果为研究大脑中缠结构象和 tau 病理学背后的复杂细胞机制开辟了一条新途径。